Genetic modification of hematopoietic stem cells (HSC) offers the potential of reconstituting immune function in HIV-infected individuals with a lifelong source of hematopoietic cells resistant to HIV infection. However, retroviral vectors based on Moloney murine leukemia virus (MLV) have proved to be relatively inefficient in transducing primate HSC, in large part due to the inability of these vectors to transduce quiescent different hematopoietic cells, including hematopoietic stem cells. However, demonstrating of the efficacy and safety of these vectors for human clinical trials will require in vivo studies in non-human primates. Recent collaborative work between our laboratory and Dr. Strayer's laboratory has demonstrated quite efficient transgene in progeny T cells derived from transduced CD34+ cells. The overall objective of this project is to examine the ability of SV40-based vectors encoding a variety of different genes that inhibit SIV and SHIV replication to transduce rhesus macaque HSC and to protect hematopoietic progeny from SIV infection both in vitro and in vivo. Specific aims include: 1) To examine the efficacy of SV40-based vectors in delivering in inhibitory genes to rhesus hematopoietic cells in vivo; and 3) To examine the ability of SV40-based vectors to inhibit SV/SHIV replication in vivo in rhesus macaques. These studies should provide valuable information. regarding the safety and efficacy of SV40 vectors for stem cell gene therapy for AIDS.